Page 63 – Practical Gastro

We report the case of a 62-year-old female with a history migraines and non-steroidal anti-inflammatory drug (NSAID) use who presented to the emergency department with epigastric abdominal pain associated with intermittent nausea and vomiting for two months. Initial esophagogastroduodenoscopy (EGD) revealed a pyloric channel ulcer and pyloric stenosis with inability to pass a standard upper endoscope. The pyloric stenosis persisted after 10 weeks despite discontinuation of NSAIDs, initiation of twice daily proton pump inhibitor (PPI) and serial balloon dilations. The pyloric narrowing was subsequently treated with the application of a needle knife papillotome to all four quadrants and a second pyloromyotomy two months later. Repeat EGD at four months revealed a widely patent pylorus and the patient was asymptomatic at the time of this endoscopy.

Kimberly J. Kolkhorst, DO Jeffrey Gill, MD, University of South Florida, Department of Gastroenterology, Tampa, Florida

INTRODUCTION

Benign pyloric stenosis, often occurring in the setting of peptic ulcer disease, may result in stricture of the pyloric channel causing patients to present with symptoms of gastric outlet obstruction. Currently, balloon dilation is the primary method of endoscopic treatment with progression to surgical myotomy in patients that are not relieved of their symptoms. Newer evidence suggests that needle knife papillotome pyloromyotomy, a novel endoscopic technique, may be used to successfully treat this condition.

Case Report

A 62 year-old female with a past medical history of nonsteroidal anti-inflammatory (NSAID) use and migraines presented with epigastric pain associated with intermittent nausea and vomiting of two months duration. She admitted to a five pound weight loss over the symptomatic time period. Esophagogastroduodenoscopy (EGD) using a standard upper endoscope revealed a narrowed pyloric channel with inability to pass the endoscope (Figure 1). Subsequently, a pediatric endoscope achieved passage through the pyloric stenosis and a 1 cm ulceration was visualized within the pyloric channel. The remainder of the stomach, duodenal bulb and second portion of the duodenum appeared normal. Biopsies from the pyloric channel were negative for Helicobacter pylori and malignancy. Omeprazole 40mg twice daily was initiated and the patient was instructed to abstain from NSAIDs for two months. However, despite medical treatment, her symptoms of epigastric pain, nausea and vomiting persisted.

Repeat endoscopic exam at two months revealed persistent pyloric stenosis again with the inability to pass the standard endoscope. The pyloric channel was dilated using through-the-scope (TTS) balloons from 10 to 12 mm for 60 second durations. Despite producing an appropriate mucosal tear, the endoscope still would not pass the stenosis and her symptoms remained unchanged. Continued pyloric stenosis was again noted at the follow-up endoscopy at two weeks, and additional TTS dilation, this time to 15mm, was performed. The TTS dilation was not successful and therefore, a needle knife papillotome was used to perform a pyloromyotomy by applying the knife to all four quadrants of the pylorus. Upon evaluation at two months, the patient’s symptoms had improved, but still persisted and, on EGD, the standard endoscope still would not pass the stricture. A second pyloromyotomy was performed with the needle knife papillotome (Figure 2), along with TTS balloon dilation to 18mm (Figure 3). At four months, the patient was finally asymptomatic, and the standard endoscope passed easily through a patent pylorus (Figure 4).

Discussion

Pyloric stenosis is an uncommon condition with various etiologies including congenital hypertrophic pyloric stenosis, malignant pyloric stenosis and benign pyloric stenosis. Congenital hypertrophic pyloric stenosis usually presents in children. Malignant pyloric stenosis is seen more in adults and is associated with primary gastric cancers or metastatic lesions. Benign pyloric stenosis is often seen in adults and due to scarring from chronic peptic ulceration or, as in the case presented above, secondary to NSAID use. Patients with pyloric stenosis may present with symptoms of gastric outlet obstruction. Standard treatments include endoscopic balloon dilation, surgical pyloroplasty or surgical distal gastrectomy.¹ Endoscopic balloon dilation is considered first-line therapy for benign cases of pyloric stenosis.² Pyloric stenosis that is refractory to two dilations is considered high risk for endoscopic failure and, as a result, surgical intervention is often recommended.²

Needle knife papillotome electroincision of strictures was first applied to refractory Schatzki rings³ and later to esophagogastric and colocolonic anastomotic strictures.^4,5 The technique was described for endoscopic pyloromyotomy in infants with congenital pyloric stenosis in 2005 with 100% success rate.⁶ Peroral endoscopic pyloromyotomy (POP) is a similar technique that has been successfully performed in patients with medication refractory gastroparesis ^7,8 and in pigs with pyloric stenosis.⁹

Bleeding and perforation are potential complications of endoscopic pyloromyotomy; however, all previously documented procedures were performed by experienced therapeutic endoscopists and were without complication. The benefits to endoscopic pyloromyotomy, as compared to surgical pyloromyotomy, include lack of inpatient hospital stay, lower healthcare costs, no surgical scars or wound infections, no risk for the development of surgical adhesions and the ability to re-start per oral intake immediately.

Our case report is the first documented use of needle knife papillotome pyloromyotomy in an adult patient with refractory, benign pyloric stenosis and demonstrates the minimally-invasive, effective and safe utility of this technique.

Gastrointestinal Motility And Functional Bowel Disorders, Series #19

Rumination Syndrome: An Update on Diagnostic and Treatment Strategies

Mena Milad,

Richard W. McCallum

Rumination syndrome (RS) can occur as a primary disorder or as a conditioned response in the setting of other vomiting disorders, particularly gastroparesis. This article will focus on the importance of history taking to diagnose rumination syndrome and review treatment strategies including breathing and relaxation skills. In addition, we emphasize a new approach, jejunostomy tube placement in patients with the most severe symptoms.

Rumination syndrome is a disorder characterized by the regurgitation of swallowed food with the decision to re-swallow the material or vomit within minutes after eating. Rumination syndrome can occur as a primary disorder or as a conditioned response in the setting of other vomiting disorders, particularly gastroparesis. This article will focus on the importance of history taking to diagnose rumination syndrome and review treatment strategies including breathing and relaxation skills. In addition, we emphasize a new approach, jejunostomy tube placement in patients with the most severe symptoms.

Mena Milad, MD, Gastroenterology Fellow, Texas Tech University Health Sciences Center Richard W. McCallum MD, FACP, FRACP, FACG, AGAF, Department of Internal Medicine, Director, Center for Neurogastroenterology and GI Motility, Texas Tech University, Paul L. Foster School of Medicine El Paso, TX

INTRODUCTION

Rumination syndrome (RS) is a unique, functional gastroenterological disorder characterized by effortless post-prandial regurgitation. The first reports of this syndrome were in the early 17th century culminating with a Mauritian physiologist and neurologist who acquired the condition after swallowing sponges tied to a string to measure gastric pH.^1,2 This distinct entity has been well described in the recently published Rome IV criteria (Table 1)³ and is diagnosed based on clinical symptoms in the absence of structural disease. Lack of awareness of the disease often prompts extensive, costly and time-consuming testing and inappropriate medical management without establishing a diagnosis. With understanding of the disease process and of the treatment paradigms, good outcomes and symptom resolution can be achieved.

CASE EXAMPLE

An otherwise healthy 47 year-old Caucasian male presented with a chief complaint of nausea, vomiting and worsening intolerance to oral intake over the past two years. The patient reported that his symptoms started soon after he was robbed at gunpoint followed by a difficult divorce. Careful questioning elicited that he regurgitates his food, recently progressing to water and fluids, within five minutes of eating. He has experienced a 20-pound unintentional weight loss over the two years and has 8-10 emergency department visits annually for nausea and vomiting, abdominal pain, hypokalemia and dehydration. The patient reported that his emergency department visits have become more frequent with multiple admissions requiring anti-emetics and occasional opioids. None of these admissions were for hematemesis, melena or hematochezia. He has seen multiple physicians, has taken many anti-emetics (including ondansetron, promethazine, metoclopramide as well as hydrocodone-acetaminophen) and recently started using marijuana with some resolution of his symptoms. He experiences gastroesophageal reflux (GERD) after his regurgitation episodes which responds to proton-pump inhibitor (PPI).

As part of the workup prior to his referral, the patient had multiple computed tomography (CT) scans of his abdomen and pelvis and laboratory evaluation

[including thyroid stimulating hormone (TSH) levels,
early-morning cortisol, complete blood count and
complete metabolic profile]

, all of which were normal. Several gastric emptying studies were attempted, but the patient regurgitated the meals immediately. Upper endoscopy revealed mild esophagitis with a normal stomach and duodenum. Routine biopsies revealed H. pylori which was successfully treated.

The diagnosis of rumination syndrome was made based on his symptoms in the setting of a negative evaluation. He was started on nortriptyline, titrated to 50 mg before bed, as well as tramadol for pain control. He was provided with instructions for breathing techniques and tapes for relaxation to precede and accompany eating in order to overcome the rumination reflex. Despite these measures, he continued to present to the emergency department with nausea, vomiting, dehydration and weight loss, and was becoming increasingly depressed. The decision was made to place a jejunostomy feeding tube laparoscopically given his failure to respond to the abovementioned treatments. Gastric wall biopsies taken during the surgery to evaluate the interstitial cells of Cajal as well as the myenteric plexus and smooth muscle were histologically normal.

The patient was placed on nightly tube feeds and daily relaxation and breathing techniques allowing him to slowly increase the content of his diet. He experienced weight gain, while medical and psychological therapy improved his oral intake to ultimately allow jejunostomy tube removal after four months. A four-hour gastric emptying study was then able to be performed and was normal.

EPIDEMIOLOGY

Rumination syndrome (RS) is well recognized in infants and mentally handicapped individuals with a prevalence between 6 and 10%.4 In adults, RS remains an underdiagnosed entity with limited awareness among patients as well as physicians. It is known, however, that RS is more prevalent in young adults with females being more affected than males.5

MECHANISMS

Although the exact pathophysiology of RS in humans is not completely understood, it is currently believed to be an unconscious, learned disorder. The rumination episodes involve relaxation of the diaphragm combined with contraction of the abdominal muscles. The lower esophageal sphincter (LES) pressure is overcome by the increase in intraabdominal and intragastric pressure. Initially, this manifests as belching (burping) that evolves into episodes of effortless regurgitation of food and liquids.⁶ Patients have a choice, usually dictated by the social setting, to either vomit the regurgitated material if they are in a place to do so, or re-swallow the material to avoid embarrassment and delay regurgitation until they are in an appropriate setting. This process is voluntary, but not intentional. Patients are unaware that they are contracting their abdominal muscles, which leads to complaints of substantial epigastric abdominal pain. Essentially, the patient is “trapped” in this post- prandial reflex and their stomach has been programmed to respond to oral intake in this manner at every meal, every day.

DIAGNOSIS

A thorough history is important in differentiating RS from other disorders. The average time from onset of symptoms until the diagnosis of RS is approximately 17 months.⁷ Patients undergo expensive, unnecessary, and sometimes invasive testing prior to being diagnosed. Rumination can be a “primary” or a “secondary” disorder associated with states of chronic nausea and vomiting, such as gastroparesis.

The onset of primary rumination syndrome is usually preceded by a stressful life event, such as loss of a family member, job loss, financial hardship, relocation, relationship hardships including divorce and others. Primary rumination syndrome episodes occur daily with each meal. Often patients will avoid or skip meals as they do not wish to vomit in front of family and friends. Over time, the decreased oral intake leads to a gradual weight loss (83%) and dehydration, resulting in visits to the emergency department or primary care physician.⁷ Hypokalemia is a result of regurgitating acidic, potassium-rich gastric contents in addition to the ingested material. In women with longstanding RS, weight loss can be associated with accompanying amenorrhea, often signaling severe disease. These patients may continue to work but over time cannot sustain the stamina to do so. Diagnostic testing may be limited since it can be difficult to obtain a gastric emptying study in patients with rumination because they often vomit the meal immediately or within 20 minutes after ingestion.

In the secondary form of RS, or conditioned vomiting, the organic vomiting disorder conditions the patients to expect and experience postprandial vomiting. Gastric emptying is delayed in up to 40% of patients with RS. ⁸ As opposed to typical gastroparesis, where vomiting usually occurs 2-6 hours after eating, in conditioned vomiting it occurs within 5-20 minutes. Stress is usually superimposed in this clinical setting of diabetic or idiopathic gastroparesis. The appearance of RS in the background of gastroparesis can be misinterpreted as a failure of treatment of gastroparesis and rumination will persist despite aggressive gastroparesis therapy, including placing a gastric electrical stimulator

Additionally, in gastroparesis, vomiting is usually preceded by a history of early satiety, nausea, fullness, and inability to finish meals and sometimes dry heaving, aspects that are not present in RS.

In both types of rumination syndrome, there is accompanying heartburn, due to refluxed material contacting the esophageal mucosa during the regurgitation event, and PPIs may be beneficial. Unlike true GERD, there is a lack of nighttime symptoms as there is no food or liquid intake at those times. This timing aspect and lack of nocturnal symptoms is what differentiates RS from gastroesophageal reflux disease.

In the differential diagnosis of RS, one must consider bulimia or anorexia. The history of these disorders includes a long history of struggling with food and weight. Additionally, the onset of vomiting is not readily identified with life events and is not related to the clinical setting of the gastroparesis or diabetic milieu. These patients, usually female, may report they began to vomit in high school and college years. In contrast, RS patients are not usually focused on weight loss and are generally motivated to seek treatment and return to a functional lifestyle.

Laboratory evaluation including a complete blood count, a complete metabolic profile and a thyroid stimulating hormone level can help exclude other etiologies of the patients’ presentation. Screening for celiac disease is important in the setting of weight loss. Vitamin B12 and folate levels may also aid in assessing evaluating malnutrtion.

Hypokalemia, not usually present in gastroparesis, often suggests the diagnosis of RS. Performing an esophagogastroduodenoscopy (EGD) will exclude peptic ulcers and H. pylori in patients with abdominal pain and right upper quadrant ultrasound will evaluate for symptomatic cholelithiasis.

While the diagnosis of rumination syndrome relies on thorough history and physical, invasive testing at a tertiary care facility may assist in eliminating the uncertainty regarding the diagnosis or unwillingness by the patient and/or the family to accept this diagnosis. Recently, high resolution manometry with intragastric pressure and esophageal impedance measurement has been used to confirm that regurgitation from the stomach is ascending towards the mouth (Figure 1). Impedance testing evaluates for regurgitation events associated with increased intragastric pressure coordinated with transient LES relaxations. However, pH testing for reflux is not recommended since acid in the esophagus is the result of rumination, not a cause of the symptoms. If performed, however, a fall in pH to less than 4.0 will be seen briefly postprandially when a rumination event occurs, but no pH changes occur overnight while the patient is fasting. Antroduodenal manometry has traditionally been the final test of choice to diagnose rumination syndrome, but is only available in a few academic settings. This test involves fluoroscopically placing a manometric catheter into the small intestine with ports to measure pressure at the antrum, duodenum and proximal jejunum. A simultaneous increase in pressure at all recording levels following oral intake is a signal that a rumination event with abdominal muscle contraction has occurred and is termed an “R-wave” (Figure 2). It is important to note, however, that this test is not necessary to diagnose RS.

TREATMENT METHODS

A multidisciplinary team consisting of the gastroenterologist, nutritionist and mental health specialist is recommended to manage rumination syndrome. These different approaches address breathing techniques, relaxation, meditation, as well as pharmacologic approaches for inducing improvement and, over time, cessation of rumination.

Relaxation/Meditation Techniques

Initially, the physician needs to establish a rapport and trust with the patient. Patients with rumination syndrome often have undergone many tests and have seen multiple physicians without fully understanding their pathology. Despite negative evaluations and endoscopies, patients continue to experience symptoms leading to frustration. Reassurance and education are key for the patient and their families. Diagrams explaining the anatomy and physiology of the upper gastrointestinal tract may be utilized; an explanation of the negative results should be included. A conversation regarding the patients’ expectations is paramount. ⁹

The mainstay of treatment in RS consists of behavioral therapy focusing on breathing and relaxation techniques. These are more successful when performed by a mental health specialist. Breathing techniques are based on habit reversal and properly creating a competing response to the behaviors of regurgitation thus distracting to reduce the targeted regurgitation events.¹⁰

Breathing techniques begin with diaphragmatic breathing as patients begin a meal. Patients are asked to sit in a relaxed, upright position. The patient then places one hand on the chest and the other hand on the abdomen. The goal is to take slow, deep inspirations by moving only the abdomen without moving the chest.^11,12 Calm diaphragmatic breathing is performed throughout the meal and at least 3-10 minutes after the meal allowing enough time for food to pass to a more distal area of the stomach.

Combined with diaphragmatic breathing, relaxation techniques play an important role in the treatment of RS. Auditory media for relaxation are commonly available to help the patient intentionally relax.¹²

After successful consumption of small snacks, the patient’s diet should be advanced slowly in a stepwise fashion to more challenging volumes.

These approaches take weeks to months to master since the entire eating process requires reprograming of the gastric response. And while most patients improve their functional level and quality of life occasional relapses can still occur, particularly during periods of stress.

Pharmacologic Therapy

Proton pump inhibitors may be required for protection of the esophageal mucosa. Antiemetic medications such as ondansetron or promethazine are required for break- through symptoms. Tricyclic anti-depressants (TCA) play a role in decreasing gastric hypersensitivity, the sensation of fullness and abdominal muscle pain, in addition to decreasing gastric sensitivity.^13,14 TCAs (e.g. nortriptyline) may be titrated started at 10 mg at bedtime and maybe titrated up to a range of 50 mg to 100 mg at bedtime with caution to avoid somnolence, fatigue or drowsiness. Doxepin may be substituted in the setting of somnolence. Baclofen (10 mg before meals) reduces the number of transient relaxations of the lower esophageal sphincter, thus decreasing the gastric volume being regurgitated. Studies show positive evidence of decreased post-prandial events on high- resolution manometry impedance recordings during Baclofen therapy, which corresponded to decreased symptoms.¹⁵

NUTRITIONAL SUPPORT

Behavioral therapy for rumination syndrome can take weeks to months to achieve its full effect.

Nutritional support prevents the complications including dehydration, vitamin deficiencies and marked hypokalemia which may require frequent hospitalizations. In patients awaiting response to behavioral therapy, a temporary jejunostomy tube provides enteral nutrition while bypassing the stomach. This aggressive approach improves quality of life, allows patients to concentrate on breathing treatments, return to work and overall become more functional. The jejunostomy tube may be placed laparoscopically, endoscopically or by interventional radiology depending on the center. Percutaneous endoscopic gastrostomy with jejunostomy combination is not recommended since oral intake is being encouraged and the presence of a feeding tube in the pylorus limits pyloric diameter and gastric emptying. The benefit of laproscopic placement is the ability to obtain a full thickness biopsy of the gastric wall to assess the status of the gastric smooth muscle, interstitial cells of Cajal and enteric neuronal plexus. This histology will be normal in primary RS but may be abnormal in RS accompanying gastroparesis. Patients need to be motivated to attempt two to three meals per day while practicing the breathing techniques and receiving their jejunostomy tube feeding at night to maintain weight and micronutrients. An increased patient weight prompts decreased nocturnal feeding. As success is achieved, the jejunostomy tube can be clamped and subsequently removed usually within three to six months.

TAKE HOME PEARLS

Rumination syndrome, in our experience at a motility referral center, is the most underdiagnosed and underappreciated etiology of unexplained vomiting and is seen weekly in our practice. The diagnosis is made by a careful history with focus on timing of the post-prandial regurgitation, which is fountain-like and effortless with the regurgitated material being re-swallowed or vomited. At the same time, an effort to identify the precipitating stressful event must be pursued. The focus of treatment is using breathing and relaxation techniques to distract patients as they attempt to eat small meals. A close relationship between the doctor and the patient is paramount in the treatment of this disease and a mental health specialist may be required to maximize the relaxation training as well as address the underlying provocative event. In addition, a pharmacologic approach with a TCA for gastric sensitivity and abdominal pain is important. Physicians should also recognize the subset of patients in whom a feeding jejunostomy tube is necessary to maintain nutrition and electrolyte balance while the patient masters the breathing and relaxation approaches, slowly increasse oral caloric intake and finally overcomes the rumination reflex.

Gerd In The 21St Century, Series #25

Achalasia: Common Features of an Uncommon Disease

Mohamed Khalaf,

Donald O. Castell

Primary achalasia is a rare worldwide disease with prevalence of eight cases per million population. Manometry is considered the gold standard for diagnosis. Achalasia is incurable in that no treatment can restore the neuronal degeneration; therefore, therapy is aimed at opening the poorly relaxed LES. Here we review the evidence which shows that pneumaticdilation (PD) and surgery are equally effective, with PD having a slight edge. We believe that using PD as initial therapy and saving myotomy as a rescue approach is the preferred overall approach.

Achalasia is a primary esophageal motility disorder characterized by absence of esophageal peristalsis and poor relaxation of the lower esophageal sphincter (LES). Primary achalasia is a rare worldwide disease with prevalence of eight cases per million population. Absence of peristalsis results from degeneration of nitric oxide releasing inhibitory neurons in the esophageal wall. Dysphagia is the most common symptom of achalasia; however, regurgitation and heartburn are frequently present. Manometry is considered the gold standard for diagnosis. Achalasia is incurable in that no treatment can restore the neuronal degeneration; therefore, therapy is aimed at opening the poorly relaxed LES. Evidence shows that pneumaticdilation (PD) and surgery are equally effective, with PD having a slight edge. We believe that using PD as initial therapy and saving myotomy as a “rescue” approach is the preferred overall approach.

Mohamed Khalaf, MD, Esophageal Motility Research Fellow Donald O. Castell, MD, Director of the Esophageal Disorders Program, Digestive Disease Center, Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, SC

INTRODUCTION

Disorders of esophageal motility are often pursued as an explanation for a variety of upper gastrointestinal symptoms. These include: dysphagia, regurgitation, heartburn and even non- cardiac chest pain. Early radiographic contrast studies demonstrated that many patients with persistent progressively worsening dysphagia showed a classical narrow closure at the esophagogastric junction (EGJ), the so called “bird beak”. Because of the failure of this segment to relax or open during swallowing the term achalasia (from the Greek; “without relaxation”) was applied.

Definition

Achalasia is a primary esophageal motility disorder. The diagnosis is confirmed manometrically by absence of esophageal peristalsis and poor relaxation of the lower esophageal sphincter (LES). The disease is suggested clinically by dysphagia and regurgitation of undigested food and; radiographically by esophageal dilation, with air-fluid level in mid-esophagus and narrowed esophagogastric junction (EGJ), “bird-beak” appearance; and endoscopically by dilated esophagus with retained fluids and undigested food remnants.^1-3

Epidemiology

Primary achalasia is a rare disease with prevalence of eight cases per million population with an incidence of about 0.3-1.63 per 100,000 per year. The incidence is equal in both sexes, but higher in older age groups with the mean age of diagnosis of about 50 years. Also, due

to the chronic nature of the disease, achalasia apparently has an increasing prevalence with stable incidence with age^4-6

Etiology & Pathogenesis

With the development of accurate intraluminal pressure- sensing probes in the 1950s not only was the pressure defect at the EGJ confirmed but the associated loss of peristalsis was recognized. This helped clarify the pathophysiology underlying the severe and progressive symptoms of dysphagia, regurgitation and weight loss that characterize this entity; worldwide in its occurrence as THE esophageal motility disorder.

More recent manometric technologies with high resolution and colourful 3D pressure displays have expanded awareness of the possibility of 3 distinct subtypes of achalasia.

Esophageal peristalsis and LES relaxation are coordinated by the nitric oxide releasing inhibitory neurons of the myenteric plexus. These neurons are absent in primary achalasia resulting in absent peristalsis and defective LES relaxation. The underlying pathogenesis remains unclear, but recent pathological and genetic studies attributed the disappearance of myenteric inhibitory neurons to chronic ganglionitis resulting from an autoimmune response against these neurons triggered by an environmental factor likely viral (particularly HSV-1) in genetically susceptible individuals. This is supported by observations that found association between achalasia with HLA-DQ?1, DQa1 and detection of circulating antibodies to the myenteric neurons. It is worth saying that the end result esophageal pathology is irreversible. Also, an association was found with some genetic syndromes like Down and Allgrove syndrome (also known as triple A syndrome, i.e. alacrima, achalasia, adrenocorticotropic hormone deficiency) suggesting the role of genetic factors.^7-11

Clinical Picture

Dysphagia is the most common symptom of achalasia (>90%). Usually, it is for both solid and liquids from the start. On the other hand, mechanical obstruction due to malignancy or stricture also leads to progressive dysphagia, evolving from solids in the beginning to solids and liquids. Regurgitation and heartburn were frequently present. Patients are often treated with acid suppressive medications assuming that these symptoms are due to gastroesophageal reflux disease (GERD). Heartburn in achalasia is explained by stasis and of undigested food in the esophagus secondary to poor esophageal clearance, rather than by real GERD. This misdiagnosis and poor response to acid suppressive medications can lead to the risk that some of these patients may be advised to have a fundoplication. Other symptoms of achalasia include weight loss, cough and chest pain especially in type III achalasia.^5,12,13

The Eckardt score¹⁴ based on grading of the achalasia symptoms can be used in the initial evaluation of the severity of the condition, as well as in the post- treatment follow up.² It is calculated by summation of the corresponding score for each symptom of dysphagia, regurgitation, and chest pain (with a score of 0 for absence of symptoms, 1 for occasional symptoms, 2 for daily symptoms, and 3 for symptoms at each meal) and weight loss (with 0 for no weight loss, 1 for a loss of <5 kg, 2 for a loss of 5 – 10 kg, and 3 for a loss of >10 kg).¹⁵ There are other conditions that can mimic achalasia both clinically and on investigations (manometry, endoscopy, and radiological studies). These conditions are called pseudoachalasia or secondary achalasia which is most commonly caused by malignancy at the EGJ either by invading the esophageal neural plexuses directly or by paraneoplastic mechanism. Less common causes are metastatic disease, infection with the protozoan parasite Trypanosoma cruzi (Chagas disease), and iatrogenic like post fundoplication and gastric banding.^16,17 Pseudoachalasia should be suspected when some clinical characters are different ( short duration of symptoms; advanced age; rapid and marked weight loss; resistance to passing the endoscope through the gastroesophageal junction, and expected treatment outcomes are not achieved. Thus, careful endoscopic assessment of the gastric cardia on retroflexed view to rule out malignancy should be done.¹²

Investigations

Manometry is considered the gold standard for diagnosis of achalasia. EGD and barium esophagram are complimentary methods to support the diagnosis of achalasia and for exclusion of structural lesions.^1,18 Achalasia can be diagnosed using conventional or high resolution (HRM) manometry systems. According to conventional manometry 2 types of achalasia have been identified, classic and vigorous. The manometric criteria of classic achalasia are: (1) absent peristalsis in the body of the esophagus characterised either by simultaneous esophageal contractions with amplitudes <40 mm Hg or by no apparent esophageal contractions and (2) incomplete relaxation of the LES. Vigorous achalasia is characterised by simultaneous esophageal contractions with amplitudes >40 mm Hg. ¹⁷

In HRM: achalasia is classified according to the latest version of the Chicago classification¹⁹ into: types I, II and III. Table 1 shows the diagnostic criteria of the 3 types in comparison to the corresponding description of the previous conventional classification.

Also, the use of multichannel intraluminal impedance with esophageal manometry (MII-EM) allows functional esophageal assessment and identifies chronic fluid retention. ²⁰

Endoscopy and barium esophagram are essentially used for exclusion of mechanical obstruction and pseudoachalasia due to tumours at the EGJ. EGD findings in achalasia are non-specific; it might show dilated esophagus and food retention in advanced cases. Barium swallow can show these features: (1) dilated esophagus; (2) air-fluid level in the mid- esophagus; and (3) narrowed EGJ giving the classic “bird-beak” appearance. Occassionally, barium study can demonstrate an extreme cork screw appearance indicating esophageal spasm associated with type III (vigorous) achalasia.^5,15,21

Computed tomography (CT) and endoscopic ultrasound (EUS): In cases of suspected pseudoachalasia for detection of masses, esophageal mural thickening or infiltrating lesion.^16,22

Treatment

Achalasia is an incurable disease in that no treatment can restore the neuronal degeneration of the esophageal wall. Therefore, therapy is aimed at opening the poorly relaxed LES. This will improve the esophageal clearance and emptying in the upright position by gravity, leading to symptom relief.²³ The treatment options available are:

1. Pharmacological Therapy

Nitrates (isosorbide mononitrate) and calcium channel blockers (nifedipine) are the most common drugs used for temporary decrease of the LES pressure. Both causes smooth muscle relaxation either by increasing the nitric oxide levels or by blocking the calcium necessary for smooth muscle contraction. They can achieve short- term relief of symptoms, however the clinical response is partial and with decreased efficacy over time.²⁴

Both drugs can cause dizziness, headaches and pedal edema. These side effects in addition to short duration of action and decreased efficacy over time are the primary causes limiting their use to high risk patient in favor of more effective treatment options (endoscopic or surgical).²⁵

Some studies showed that phosphodiesterase inhibitors (Sildenafil) causes significant decrease in the LES pressure suggesting its use in clinical practice, nevertheless, comparative studies are lacking.²⁶

2. Botulinum Toxin (Botox)

Botox (BTX) is a potent toxin that inhibits the release of acetyl choline from nerve endings leading to paralysis of the innervated muscle. It is injected endoscopically using a sclerotherapy needle in all four quadrants of the LES 1-2 cm above the Z- line. The total dose injected is from 80 – 100 U.^27,28

76% of achalasia patients will respond to one Botox injection with 50 % recurrence of symptoms within 6 months. These studies suggest consideration of a trial of another injection since 75% of patients can respond to the second injection.²⁵ Because of this high recurrence rate; our practice is to use BTX in high risk patients or in patients refusing or fearing to have pneumatic dilation or surgical myotomy.

BTX can be tried before proceeding to pneumatic dilation and also can be given in cases of failed dilation. Some studies in the surgical literature indicate that BTX injection before myotomy can lead to increased rate of surgical failure because of the scarring produced by the toxin on the LES muscle layer, however evidence shows that it can be used in cases of surgery failure.²⁹ Contraindications of Botulinum toxin include egg allergy and Lambert Eaton syndrome. Also it should be used cautiously in patients receiving aminoglycoside antibiotics as it can potentiate the toxin effect.³⁰

3. Pneumatic Dilation (PD)

This endoscopic technique aims to produce a controlled tear in the muscular layer of the LES by forceful stretching using an air-filled balloon. This method improves esophageal emptying and so relieves the symptoms. The most common balloon used for this purpose is the Rigiflex balloon dilator (Boston Scientific Corporation, Boston, MA, USA). It is a 10 cm long balloon made of polyethylene polymer and comes in 3 diameters (30, 35 and 40 mm). The balloon has 4 radiopaque markers helping in identifying the balloon borders under fluoroscopic guidance; radiopaque markers at each end of the balloon, and another 2 markers identifying the middle.^2,5,31

The technique involves careful endoscopic examination of the esophagus and to determine the location and gross appearance of the LES. It may show puckering and opens by gentle pressure with the endoscope. If forceful pressure is needed, one should suspect pseudoachalasia. The EGJ should be examined carefully with retroflexion inspection of the cardia to exclude pseudoachalasia. The findings expected to be in the esophagus are: esophageal dilation and retained fluid/food residues. The mucosa may show redness, friability and cracked appearance due to prolonged stasis.³¹

After endoscopic examination, we withdraw the scope and insert the balloon blindly over a Savary wire. The key of a successful dilation is to accurately place the balloon across the EGJ while the patient is in the supine position.²⁵

Our practice is to inflate the balloon to 10 psi. The duration of inflation is less than 15 seconds, however it is not as important as observing that the “waist” is obliterated during fluoroscopy.³²

Figures 1 and 2 show fluoroscopy images during PD procedure.

Then we withdraw the balloon (blood on it indicates mucosal tear but not necessarily a successful dilation), and place a NG tube to perform a gastrographin study under fluoroscopy to detect early perforation.³¹

Afterwards we put the patient under observation for 2 hours before discharge. We reassess the patient after one month using the clinical response and the Eckardt symptom score. If the patient has a score of 3 or less, we consider this a success; otherwise, we proceed with dilation using the next larger diameter balloon until achieving clinical remission.

This approach of graded dilations has a documented initial clinical remission rate in 90% of patients, and probability of remaining in remission without further dilations at 5 and 10 years is 67% and 52%, respectively. Also, performing repeated dilations on demand of symptom recurrence increases the 5 and 10 year remission rate to 97% and 93% respectively. It is our belief that PD is the most cost-effective treatment for achalasia over a 5-10-year follow up period with an overall perforation rate of less than 2%.^2,25,33

Surgical Cardiomyotomy (Open or Laparoscopic)

Open surgical myotomy was first described by the German surgeon Ernest Heller.³⁴ Now, it is widely replaced by the laparoscopic approach which was first performed by Cuschieri et al.³⁵ Laparoscopic Heller myotomy (LHM) has the advantages of being less invasive, lower morbidity and shorter hospital stay than the open approach. To curtail the resulting reflux, addition of a partial fundoplication (Dor or Toupet) rather than a full Nissen fundoplication as an anti-reflux procedure shows good results with less postoperative GERD and dysphagia.³⁶

Successful esophageal myotomy lowers LES pressure by up to 75%, markedly improves esophageal emptying and decreases the esophageal diameter.²⁵

The overall complication rate of LHM is about 6% with reported mortality of 0.1%, hence LHM combined with partial fundoplication is considered a safe operation.⁵

Data are lacking to demonstrate how many operations are needed to ensure competency of the surgeon performing LHM. Sharp et al. reported that in a series of 100 operations, most of the complications occurred in the first 50.^25,37

Early recurrence of dysphagia can develop in up to 31% of cases within 12-18 months after surgery and is usually caused by incomplete myotomy, excessive scarring or tight anti-reflux wrap. Management of LHM failure can usually be done conservatively by pneumatic dilation.^25,38,39

Esophagectomy

This may be necessary in cases of megaesophagus with esophageal diameter >6 cm or if tortuosity (sigmoid esophagus) is hindering emptying. The reconstruction options after esophageal resection are gastric pull-up or long segment colonic interposition. Most surgeons prefer the gastric pull-up because it requires only one anastomosis to be done.⁴⁰

Figure 3. Barium esophagram showing sigmoid configuration of the esophagus.

Per Oral Endoscopic Myotomy (POEM)

It seems that even as we appear to have settled some age-old questions the equation is being changed by the new kid on the block, per oral endoscopic myotomy, or POEM.

Both PD and LHM are considered the “standard of care” of achalasia treatment. Recently, POEM is emerging as an alternative to LHM. POEM has the advantages of minimal invasiveness of an endoscopic procedure and the precision of a surgical myotomy.^41,42

The standard POEM steps as described by Inoue et al are (1) creation of a submucosal tunnel from 12 cm proximal to the LES to about 2-4 cm into the stomach. The submucosal tunnel is usually created on the anterior esophageal wall except in post-Heller patients in whom it is created on the posterior esophageal wall; (2) myotomy of the circular muscle fibers starting 3-4 cm distally from the first incision and 2-4 cm into the stomach wall; and (3) closure of the entry site by using endoscopic clips.⁴²

Since POEM is relatively new, only short- and intermediate-term treatment success rates are available. There were several studies that showed objective improvement in esophageal function assessed by manometry and timed barium esophagram findings after POEM (even comparable to LHM).⁴³

One of the main concerns with POEM, compared with laparoscopic Heller myotomy (LHM), is that an anti-reflux procedure is not performed concurrently. The reported incidence of reflux following POEM reaches higher than 50% in America and Western Europe.⁴⁴

PD vs. LHM

Over the years management of achalasia has revolved around discussion of preference for a “medical” or surgical approach as a definitive therapy; i.e. large balloon pneumatic dilatation (PD) versus myotomy as the means to disrupt the dysfunctional circular muscle of the LES. Each has its champions and its nay- sayers; for years there has been no high level RCT to direct treatment preference beyond opinion and “local expertise”. The recent publication in the New England Journal of a large multicenter prospectively randomized trial from across Europe has shown convincingly that the two widely used approaches are equally effective with PD having a slight edge. Maybe the popular approach of using PD as initial therapy and saving myotomy as a “rescue” approach is the best. The European experience also reminded us that PD should be performed with step-wise balloon sizes and that repeated dilations for recurring symptoms, even years apart should be considered; not the “one and done” approach of a myotomy.²

As most practicing gastroenterologists are unlikely to see patients with achalasia very often, it is difficult for them to maintain a level of appropriate expertise with pneumatic dilatation as a treatment option and patients are thus often referred for a myotomy.

Whether the inclination is for treatment of achalasia with pneumatic dilatation or LHM it is our belief that these patients should be referred to a specialist center (center of excellence) where an individual or a team actively treats patients with achalasia regularly.

The results of the European trial strongly reinforces the suggestion that the real decision should be based on what local expertise is available; that is, whether there is an individual in the vicinity who has the experience and knowledge to treat achalasia, be it by surgical or balloon dilation.

Interestingly, the rapidly evolving technique of high-resolution manometry has brought to light the concept of three subtypes of achalasia. Although no difference in outcome between Heller myotomy and PD has been noted for patients with type I and II achalasia, patients with type III disease seem to respond better to Heller myotomy than to PD.⁴⁵

To the neophyte, this observation is often considered as new. To the experienced esophagologist, however, subtyping of achalasia is just a new vision of a well-known concept. Interestingly, the European study was performed at a group of medical centers, none of which used high-resolution manometry to establish the diagnoses. Therefore, one could argue definitively that this old disease is well recognized and appropriately staged for therapy on the basis of good-quality manometry of any kind, and is not a new disease recently discovered by a new technology. Use of subtyping, perhaps made easier by the technique of high-resolution manometry, should continue to guide therapy decisions for patients with achalasia.

CONCLUSION

The European multicentre study comparing pneumatic dilation with laparoscopic Heller myotomy, along with the author’s experience of greater than 40 years as an “esophagologist”, established PD as the preferred approach for initial treatment of achalasia. We think it is appropriate to consider a referral to an esophageal expert, for either a PD or a myotomy.

Frontiers In Endoscopy, Series #29

EUS-Guided Liver Biopsy: An Emerging Diagnostic Modality

Kirby Mengert,

Douglas G. Adler

A new method of collecting liver histology is via endoscopic ultrasound (EUS) guided liver biopsy which allows the endoscopist to obtain the necessary liver histology while theoretically limiting complications for the patient. In this article we discuss EUS guided liver biopsy as a viable and safe means for assessing liver histology.

Kirby Mengert University of Utah School of Medicine, Gastroenterology and Hepatology Douglas G. Adler MD, FACG, AGAF, FASGE Professor of Medicine, Director of Therapeutic Endoscopy Director, GI Fellowship Program, Gastroenterology and Hepatology, University of Utah School of Medicine, Huntsman Cancer Center, Salt Lake City, UT

INTRODUCTION
Case Report

A 50 year old man with chronic, heavy alcohol use was referred to the hepatology clinic for evaluation. The patient had some baseline enceopahlopathy and elevated transaminases that were consistently in the 2-3x ULN range. A right upper quadrant ultrasound examination was consistent with some degree of cirrhosis. Hepatitis serologies and other tests for metabolic or genetic abnormalities were negative. The patient was referred for EGD to rule out and treat any varices and to undergo simultaneous liver biopsy by endoscopic ultrasound (EUS).

On EUS, the liver was diffusely hyperechogenic and somewhat nodular at its borders, both findings were felt to be consistent with cirrhosis. (Figure 1) There was trace ascites in the abdomen. Doppler ultrasound was used to identify and avoid any interposed vessels. A 19 gauge EUS FNA needle was used to perform liver biopsy. (Figure 2) Three passes were made into the left lobe of the liver using a transgastric approach. Several solid cores were obtained as well as some fragments of liver tissue, all of which was sent for pathologic evaluation.

Pathologic diagnosis based on tissue obtained via EUS-guided liver biopsy was read as cirrhosis in the setting of some steatohepatitis (Stage 4 out of 4), as well as minimal hepatocyte predominant iron deposition (1 out of 4). There was marked pericellular centrilobular fibrosis, as confirmed by trichrome stain. There was moderate to severe steatosis involving greater than 60% of the total hepatic parenchyma, with numerous ballooned hepatocytes and conspicuous Mallory’s hyaline. Minimal lobular chronic inflammation was identified without significant necrosis. Canalicular cholestasis was present. (Figures 3-7)

The patient was referred to hepatology for further evaluation, although he continued to consume alcohol on a daily basis despite advice to the contrary.

Discussion

Liver histology is the gold standard for diagnosing and staging parenchymal liver disease. Liver histology is commonly collected via a percutaneous, transjugular, or surgical route. Some of the limitations that occur with collecting liver biopsies via the percutaneous route include sampling error, pain, bleeding, and the puncturing of other organs. Sampling error can occur because usually when percutaneous liver biopsies are taken they are only taken from one lobe of the liver. Pain is common with the percutaneous route because sedation is often not used when taking the liver biopsy. Bleeding and puncturing other organs can also occur because percutaneous liver biopsy is a “blind” biopsy method. Limitations from taking a liver biopsy from the transjugular route included neck hematoma, hepatic arteriovenous fistula, and intraperitoneal hemorrhage.

Liver histology is an important part of assessing various hepatic parenchymal diseases. Liver histology can be collected via a percutaneous, transjugular, or surgical route. A new method of collecting liver histology is via endoscopic ultrasound (EUS) guided liver biopsy. Doppler is also used so that blood vessels can be visualized (and avoided) as well. Using real time ultrasound and Doppler images the endoscopist is able to advance an aspiration needle into the hepatic tissue while avoiding vessels, bile ducts, and other interposed structures. This allows the endoscopist to obtain the necessary liver histology while theoretically limiting complications for the patient.

A 2009 study by Dewitt at al. evaluated EUS- guided liver biopsies. In this study patients underwent an EUS-guided liver biopsy if their hepatologist referred them to have one. The patients in this study were referred for reasons such as: unexplained chronic (> 6 months) increased liver function tests, suspected hepatic steatosis, and jaundice without evidence of intrahepatic or extrahepatic biliary duct obstruction. Twenty-one patients had a liver biopsy taken with a 19 gauge spring loaded Quick-Core needle and Doppler examination was conducted before the needle pass to ensure that no vasculature or large bile ducts were punctured. A median of 3 passes per patient was taken with a range of 1-4 passes. 18 patients had their left lobe biopsied while 3 patients had both their left and right lobe biopsied. A definitive diagnosis was established from the histology specimens in 19 (90%) out of the 21 patients. All of the patients were watched for 90 minutes after their procedure to make sure that no complications arose. There were no complications during or after the procedure reported in this study.¹

A 2016 study by Pineda at al. compared histological samples retrieved from an EUS approach to those obtained via percutaneous and transjugular methods. This was a retrospective study that included 175 patients that underwent either percutaneous, transjugular, or EUS-guided liver biopsy from November 2011 to September 2013. Abnormal liver function tests of undetermined etiology, possible biliary obstruction, and imaging that showed fatty liver disease were the main indications for liver biopsy. Twenty-seven patients had a percutaneous liver biopsy while 38 had a transjugular liver biopsy and 110 had an EUS-guided liver biopsy. The EUS-guided liver biopsy specimens were collected with a 19 gauge FNA needle that was passed 2-6cm into the liver with suction from a 20mL syringe applied while the endoscopist made 7-10 actuations. This process was counted as one pass and there was a range of 1-4 passes per patient. The average total specimen length (TSL) from the EUS liver biopsy group was 38mm (Range: 24-81mm) and the average number of complete portal tracts (CPT’s) was 14 (Range: 9-27). The transjugular liver biopsy specimens were collected by interventional radiologists. Two to three needle passes into the liver were taken with an 18 or 19 gauge needle to obtain the specimens under the guidance of fluoroscopy. The average TSL from the transjugular liver biopsy group was 34mm (Range: 24-48mm) and the average number of CPT’s was 15.5 (Range: 9-21). The percutaneous liver biopsy specimens were collected with an 18, 19, or 20 gauge needle under real time ultrasound or CT guidance. The average TSL from the percutaneous liver biopsy group was 25mm (Range: 15-38mm) and the average number of CPT’s was 10 (Range: 7-16). In this study, EUS-guided liver biopsy produced significantly more tissue in terms of both TSL and CPT’s compared with percutaneous liver biopsy. Also, EUS-guided liver biopsy was shown to produce longer TSL and comparable CPT’s compared to transjugular liver biopsy. These findings lead the authors to believe that EUS-guided liver biopsy will start to be performed more frequently than other approaches.²

A 2012 study by Stavros at al. described the cost effectiveness of EUS-guided liver biopsy when combined with EUS to excluded biliary obstruction. Between July 2008 and July 2011, 31 patients were referred for EUS to rule out biliary obstruction after their liver function tests were found to be abnormal. If a biliary obstruction was found during the EUS a same session ERCP was performed. If no evidence of biliary obstruction could be found an EUS-guided liver biopsy was performed. Twenty-two (71%) of the 31 patients had no evidence of a biliary obstruction and therefore underwent a same session EUS-guided liver biopsy. A 19 gauge FNA needle was used to obtain the liver histology with the endoscopist taking a median of 2 passes per patient (Range: 1-3). The median specimen length obtained was 36.9mm (Range: 2-184.6mm) and the median CPT’s was 9 (Range: 1-73). The cause of the abnormal liver function tests could be determined via the liver histology collected in 20 (91%) out of 22 patients. There were no procedural complications associated with EUS-guided liver biopsy. The authors concluded the diagnostic yield of EUS-guided liver biopsy is comparable to other liver biopsy methods such as the transjugular approach and the percutaneous approach. The fact that EUS-guided liver biopsy provides adequate tissue samples and can provide a real time sonographic view lead the authors to state their belief that EUS-guided liver biopsy should be the preferred choice of liver biopsy technique. From a cost point of view, the authors showed that a percutaneous liver biopsy is roughly estimated to cost $815.30 while an EUS-guided liver biopsy is estimated to cost $1581.27, although EUS-guided liver biopsy allows other maneuvers to be performed at the same time (EGD, EUS, biopsies, banding, etc) so the costs are somewhat difficult to compare.³

A 2015 study by Diehl at al. observed the diagnostic yield and safety of EUS-guided liver biopsy across eight different centers. One hundred and ten patients underwent EUS-guided liver biopsy between November 2011 and September 2013 in the eight different centers. The indication for liver biopsy in these patients was previous serological and/or cross sectional imaging which were non-diagnostic for their underlying presentation and a desire for further evaluation. Each patient started with an EUS and if a biliary obstruction was found a same session ERCP was performed and if no biliary obstruction was found an EUS-guided liver biopsy was performed. A total of 110 EUS-guided liver biopsies were taken. Sixty-eight patients had both their left and right lobes biopsied, 34 had only their left lobe biopsied, and 8 had only their right lobe biopsied. All patients had a range of 1-3 passes taken per procedure. The median tissue length obtained in all 110 patients was 38mm (Range: 0-203mm) and the median CPT’s was 14 (Range: 0-68). There was no significant difference between the entire study population and the groups that had only one lobe biopsied for both total specimen length and CPT’s. One hundred and eight procedures (98%) yielded specimens adequate for diagnosis. In this study, complications were defined as any deviation from the expected post-procedure clinical course such as: bleeding, perforation, pneumothorax, bile leak, or infection. One patient (0.91%) out of the 110 experienced a complication. This one complication occurred in a patient that was both coagulopathic and thrombocytopenic. The patient presented with abdominal pain post procedure and after receiving a CT scan was found to have a pericapsular hematoma. An angiogram was performed and showed that there was no active bleeding so angioembolization was not required. The authors argued that in their opinion the high diagnostic yield combined with the low complication rate makes EUS-guided liver biopsy the preferred method of collecting liver histology.⁴

A 2013 study by Gor et al. investigated the adequacy of histology taken by a 19 gauge non-Tru-Cut FNA needle in 10 patients.⁵ Four men and 6 women underwent an EUS-guided liver biopsy between February and June 2012. All 10 patients were undergoing an EGD for reasons other than an EUS-guided liver biopsy with the two most common indications being EUS to exclude biliary obstruction and EGD to rule out varices in patients with suspected liver disease. EUS- guided liver biopsy was not the primary reason for the upper endoscopy but the added procedure only added 4 minutes (on average) to the overall procedure time. Each patient only had their left lobe biopsied with three actuations per pass and three passes per procedure. A histological sample was obtained from every patient. The average specimen length was 14.4mm (Range: 6-23mm) and the average number of CPT’s per sample was 9.2 (Range: 6-15). All of the samples collected were determined to be adequate because they all lead to definitive diagnoses. No complications occurred during or after the procedures that were included in this study. The samples collected in this study are comparable to those collected via the percutaneous or transjugular route leading these authors to believe that EUS-guided liver biopsy with a 19 gauge non-Tru-Cut needle should be considered as an acceptable way to collect liver histology, although the Tru-Cut needle is not widely utilized at this time.

Overall, EUS guided liver biopsy appears to be a viable and safe means for assessing liver histology. Limited data suggests that EUS-guided approaches can also determine portal pressures and, when this is combined with EUS-guided liver biopsy and all of the diagnostic and therapeutic potential of an EGD and EUS, demonstrate that EUS directed liver evaluations are likely to only become more widely adopted with time.^6,7

The authors wish to thank Dr. Kajsa Affolter for her help with the preparation with the pathologic figures for this manuscript.

A Special Article

Predictors of Gastroesophageal Refux Disease Evidence in Noncardiac Chest Pain: A New Management Algorithm

Philip O. Katz

In order to identify a cost-effective, organized approach to managing NCCP, we aimed to identify clinical predictors of objective evidence of GERD on endoscopy in order stratify patient risk and optimize utilization of EGDs and PPI trials in this population.

Background: In noncardiac chest pain (NCCP) patients, proton pump inhibitor (PPI) therapy is only superior to placebo at improving chest pain when there is objective evidence of gastroesophageal reflux disease (GERD) on endoscopy or pH monitoring. The current guidelines recommend referring patients for confirmatory testing prior to starting treatment.

Aims: We aimed to identify clinical factors in NCCP patients that predict the presence of GERD.

Methods: Medical records from all patients admitted to Albert Einstein Medical Center with NCCP confirmed by stress test who had undergone an endoscopy within 3 years of discharge were included and grouped in accordance to their endoscopic results. Demographics, past medical history, outpatient medication list and details from their hospital course were evaluated to determine independent predictors.

Results: Analysis of over 20 variables in 86 patients identified two positive predictors of GERD evidence on endoscopy: older age (OR 3.12; 95% CI 1.07 – 8.36) and prior disease evidence on endoscopy (OR 5.40; 95% CI 1.02 – 28.52). One negative predictor, history of coronary artery disease (OR 0.54; 95% CI 0.17 – 0.74), was also identified. With these three predictors, a scoring system was created that divided patients into indeterminate and high risk categories. High risk patients on PPI had a decrease in repeat emergency room visits and hospital readmissions compared to those not on therapies.

Conclusions: Based on these results we propose NCCP management algorithm, which, if utilized, would standardize care and optimize endoscopy and PPI allocation.

Alexandra Baumann, DO, Department of Internal Medicine¹ David Wheeler, MD, PhD, Department of Internal Medicine¹ Monil Patel, DO, Department of Internal Medicine¹ Stacey Zavala, MD, FACG² Philip O. Katz, MD, FACG, Division of Gastroenterology¹ ¹Albert Einstein Medical Center, Philadelphia, PA ²Gastroenterology Associates of SW Florida, Fort Myers, FL

INTRODUCTION

Noncardiac chest pain (NCCP) affects 25% of all adults and accounts for 2-5% of all emergency room (ER) visits. Gastroesophageal reflux disease (GERD) is the most common finding.¹ An empiric trial of a proton pump inhibitor (PPI) is the standard of practice;² however, a recent systematic review demonstrated that PPIs were not superior to placebo in reducing chest pain in patients without objective evidence of GERD (i.e. esophagitis on endoscopy or positive pH testing).³ Furthermore, the broad use of PPI therapy leads to unnecessary, costly long-term treatment and may increase the risk of Clostridium difficile infections and osteoporotic bone fractures.⁴ The latest GERD guidelines recommend that suspected GERD-related NCCP be considered for diagnostic evaluation with esophagogastroduodenoscopy (EGD) or pH monitoring before initiating a PPI trial.⁵ Yet, less than one third of NCCP patients are referred to a gastroenterologist.⁶

The current management of NCCP patients needs to be addressed due not only to the unpredictable response to PPI therapy but also to the high healthcare utilization and cost incurred by this population. It has been estimated that the cost to the healthcare system is approximately $315 million yearly due to frequent physician visits, hospital admissions, and use of medications and procedures, which is ongoing for many years.^7,8,9 The only factors shown to lower readmissions in this population despite their persistent symptoms is appropriate gastrointestinal (GI) diagnostic studies (i.e. pH monitoring, EGD, barium swallow and manometry) and patient reassurance.^10,11 However, it seems impractical to assign all patients to diagnostic testing given the prevalence of the disease.

In order to identify a cost-effective, organized approach to managing NCCP, we aimed to identify clinical predictors of objective evidence of GERD on endoscopy in order to stratify patient risk and optimize utilization of EGDs and PPI trials in this population.

METHODS
Study Population

This retrospective, case-control study was approved by the Institutional Review Board at Albert Einstein Medical Center and exempt from patient consent. The medical records of all patients who were admitted to the Cardiology/Telemetry service at Albert Einstein Medical Center (a tertiary teaching and referral hospital) between January 1, 2006 and January 1, 2008 were reviewed. Patients were included in the study if they were (1) admitted for chest pain or an equivalent diagnosis, (2) had a negative cardiac evaluation during that admission, and (3) had a subsequent EGD within 3 years. For the purposes of this study, chest pain equivalent diagnoses included: angina (413.x, 411.1), tachycardia (427.x, 785.x), acute coronary syndrome (411.x), chest pain (786.5x), heartburn (787.1), elevated troponin (790.6), shortness of breath (786.05), myocardial infarction (410.x, 861.01) and chest tightness/pressure/discomfort (786.59). A negative cardiac evaluation was defined as documentation of low risk for acute coronary syndrome and a negative stress test. Patients were excluded if they underwent percutaneous coronary intervention (i.e. cardiac catheterization) regardless of the findings due to their high pretest probability for significant coronary artery disease.

DATA COLLECTION

Demographics, past medical history, outpatient medication list and details from the hospital admission were collected from the Albert Einstein Medical Center electronic medical record. In the case of multiple admissions during the above defined time period, only the first admission was included. The frequency of repeat ER visits and readmissions to Einstein Medical Center for chest pain were also recorded. EGD reports were reviewed and noted to be positive for objective signs of GERD if they reported esophagitis, Barrett’s esophagus, and/or hiatal hernia. In the event of multiple EGDs, the findings of the EGD closest to the discharge date were included. All data was entered into an electronic database and was reviewed by two individuals to ensure accuracy.

Statistical Analysis

Patients were divided into two groups based on objective findings of GERD on EGD, and odds ratios with 95% confidence intervals were calculated for all demographic, prior medical history, outpatient medication and hospital course data. Those with significant odds ratios were analyzed using a multivariate logistical regression to confirm they were independent predictors. A scoring system based on the three validated clinical predictors (indeterminate risk <2, high risk ≥ 2) was created and evaluated with descriptive statistics including odds ratio. Rate of PPI usage and number of repeat emergency room visits and hospital admissions for chest pain were stratified by this scoring system into categories and compared with Pearson’s chi-squared test and analysis of variance (ANOVA) respectively. The number of return visits was further stratified by both scoring system and presence of PPI therapy at discharge and analyzed using a two-way ANOVA with a Bonferroni post-hoc test. Differences were considered significant for p-values less than 0.05. All statistical analysis was preformed using GraphPad Prism and SPSS.

RESULTS
Few patients diagnosed with NCCP get appropriate GI work-up.

During the study period, over 1,400 patients were admitted for chest pain or an equivalent diagnosis and underwent a stress test and cardiac evaluation. Subsequently, approximately 60% were found to have a noncardiac etiology. Only 86 patients (less than 10%) were referred to a GI specialist and subsequently underwent an EGD.

Age, history of coronary artery disease and prior GERD-positive EGD are independent predictors of objective evidence of GERD in NCCP.

To identify which NCCP patients were most likely to benefit from PPI therapy, we analyzed the clinical characteristics of the 86 patients who underwent subsequent EGD. 48.8% of patients had EGD consistent with objective evidence of GERD (i.e. (+) EGD). When the clinical characteristics of the (+) EGD and (-) EGD group were compared, three factors were significantly associated with objective findings on EGD (Figure 1). Age greater than or equal to 65 (OR 3.12; 95% CI 1.07 – 8.36) and (+) EGD in the past (OR 5.40; 95% CI 1.02 – 28.52) were both positively associated with (+) EGD while prior history of coronary artery disease (CAD) (OR 0.54; 95% CI 0.17 – 0.74) was negatively associated. Multivariate logistical regression confirmed age, history of CAD, and prior (+) EGD as independent predictors of (+) EGD (β = 1.018 p = 0.035, β = -0.749 p = 0.019, and β = 2.060 p = 0.018 respectively). Neither history of GERD nor presence of GI symptoms on admission were associated with subsequent (+) EGD.

Patients at high risk for objective evidence of GERD had fewer return ER visits and readmissions when discharged with PPI.

After establishing age, history of CAD and prior (+) EGD as independent predictors of objective evidence of GERD, we created a scoring system to divide patients into risk categories. Patients were given 1 point each for age greater or equal to 65, no prior history of CAD and prior (+) EGD such that the score ranged from 0 to 3. Using the scoring system, patients were divided into indeterminate risk (score 0-1, n=30) and high risk (score 2-3, n=56). This scoring system predicted evidence of GERD more robustly than any of the individual components alone (OR 2.31; 95% CI 1.50 – 10.06). Furthermore, it had high specificity (79.5%) and positive predictive value (70.0%) but limited sensitivity (50.0%) and negative predictive value (62.5%). The risk categories had similar rates of PPI usage at discharge (37.5% vs 50.0%, p = 0.263) and number of return ER visits and readmissions for chest pain (2.23&PlusMinus3;38 vs 2.17±2.87 respectively, p = 0.928). Interestingly, high risk patients on a PPI had a significantly lower number of return ER visits and readmissions when compared to those not on a PPI (Figure 2). Meanwhile in indeterminate risk individuals, PPI therapy did not affect repeat presentations for chest pain.

DISCUSSION

NCCP is a common clinical problem that is without a standardized, cost-effective and streamlined management algorithm. Our study established age greater than or equal to 65, past medical history of CAD and prior (+) EGD as independent predictors of objective evidence of GERD in NCCP patients. Using these three predictors we developed a scoring system to divide patients into indeterminate (score 0-1) or high risk (score 2-3) categories and proposed a NCCP management algorithm.

We identified age greater than or equal to 65 and prior (+) EGD as positive predictors of a (+) EGD in patients with NCCP. GERD and its complications (i.e. erosive esophagitis, Barrett esophagus and esophageal malignancy) are more common in the elderly so the presence of advanced age as a risk factor for GERD- related NCCP is not surprising. Furthermore, elderly patients often have atypical presentations of GERD and tend to reach advanced stages of disease before seeking treatment.¹² However, increased cardiovascular risk is also associated with age, and patients should be thoroughly evaluated for cardiac etiology before GERD-related NCCP is considered as a cause. The discovery that prior (+) EGD is an independent predictor for GERD is novel but intuitive. Unlike the reflux symptoms of GERD, GERD-induced chest pain responds modestly to PPI therapy;³ therefore, patients are more likely to discontinue prescribed PPI therapy and not have resolution of their disease.

We also identified a history of CAD as a negative predictor. In this study, we used a negative stress test as evidence to lack of cardiac disease. One limitation of stress testing is that it may not be sensitive enough to detect some cardiac etiologies of chest pain (i.e. moderate luminal obstruction and vasospasm not resulting in ischemia).¹³ Patients with known history of CAD are at much higher risk of this inaccuracy. The use of the history of CAD as a negative predictor may not have held true if more sensitive diagnostic modalities, such as cardiac catheterization or coronary computed tomography angiography, were utilized.¹⁴ This again highlights the need for a thorough cardiac evaluation prior to GI work-up.

Using the above three independent clinical predictors we developed a scoring system which divides patients into indeterminate and high risk for objective GERD findings. Given the limited sensitivity and negative predictive value of this metric, an indeterminate score of 0-1 is not sufficient to exclude the possibility of GERD. Therefore, further work-up is indicated, including EGD. In contrast, high risk patients (score 2-3) are very likely to have objective evidence of GERD. PPI therapy was associated with a 63.8% decrease in repeat hospital admissions and therefore we recommend an empiric PPI trial for this population. EGD should be reserved for those with alarm features or poor treatment response. While this algorithm is promising, this study is retrospective and single-center with a relatively small sample size; therefore larger prospective multi-center studies are needed for validation. Once validated this algorithm will standardize the physician’s approach to NCCP and optimize EGD and PPI allocation.

Colorectal Cancer: Real Progress In Diagnosis And Treatment, Series #7

A Colonoscopist’s Perspective on Serrated Lesions

Douglas K. Rex

A full understanding of the spectrum of endoscopic appearances, as well as methods of effective resection, are essential to modern colonoscopic management of serrated lesions and to effective colonoscopy. Current recommendations for surveillance colonoscopy after resection of serrated are based on limited data, and are reviewed in this paper.

Douglas K. Rex, MD, Indiana University, Indianapolis, IN

Effective detection and resection of serrated class lesions is emerging as a defining feature of superior quality colonoscopy. Serrated lesions are more likely to be missed by colonoscopists compared to conventional adenomas, and effective detection depends on a well-informed endoscopist, high quality bowel preparation and detailed mucosal inspection. Serrated lesions are also more likely to be incompletely resected compared to conventional adenomas, but this problem can be overcome by submucosal injection with a contrast agent and use of a high definition colonoscope. Endoscopists and pathologists are both reliable in classifying colorectal lesions as belonging to the serrated class vs conventional adenomas. Endoscopists can utilize the NICE classification to make this distinction. There is a high level of interobserver variation between pathologists in the interpretation of hyperplastic polyp vs sessile serrated polyp (synonymous with sessile serrated adenoma). The NICE classification does not attempt to distinguish hyperplastic polyp from sessile serrated polyp, but the recently proposed WASP classification addresses this distinction. Most sessile serrated polyps have no cytological dysplasia, but about 5% of sessile serrated polyps contain a region that is endoscopically and histologically identical to a conventional adenoma. This lesion, termed a sessile serrated polyp with cytological dysplasia, is a more advanced lesion and must be completely resected and generally followed closely. Current recommendations for surveillance colonoscopy after resection of serrated are based on limited data, and are reviewed in this paper.

Introduction
Section 1

Colorectal cancers are believed to arise almost entirely in benign growths called polyps. The conventional polyp to cancer sequence in the colorectum has been termed the “adenoma-carcinoma” sequence,¹ This paper will refer to the precursor lesions in the adenoma-carcinoma sequence as “conventional adenomas.” By definition, all conventional adenomas are dysplastic, which should be characterized by pathologists as low-grade or high-grade dysplasia. In clinical practice, when conventional adenomas are reported without the dysplasia grade specified, clinicians can assume that the adenoma had low grade dysplasia. Conventional adenomas can also be characterized as tubular, tubulovillous, or villous.²

Although every colorectal cancer has a unique molecular profile, there are 3 broad categories of molecular pathway to colorectal cancer. Conventional adenomas are the precursors of 2 of the pathways, including the chromosomal instability (CIN) pathway and the Lynch pathway (Table 1).³

In recent decades, there is increasing recognition that a third general molecular pathway to colorectal cancer arises through a precursor polyp that is distinct from the conventional adenomas.^3,4 This separate set of polyps is the “serrated class” lesions, and these lesions are distinct from conventional adenomas in their molecular profile, their histology, and their endoscopic appearance. The serrated pathway accounts for 15 to 30% of all colorectal cancers, and the prevalence of cancers arising in serrated lesions increases progressively from the left to right side of the colon. Expertise in the recognition and effective resection of serrated class lesions has become one of the main distinguishing features of a modern master colonoscopist, compared to the average or low performing colonoscopist.

Terminology of Serrated Class Lesions

The World Health Organization (WHO) recommends division of the serrated class into three subtypes, including hyperplastic polyps, sessile serrated polyp (sessile serrated adenoma), and traditional serrated adenoma (Table 2).⁵ More than 99% of serrated class lesions fall into the hyperplastic polyp or sessile serrated polyp (SSP) subtypes. The terms “sessile serrated polyp” and “sessile serrated adenoma” (SSA) are synonymous. Clinical trials have commonly designated the lesions as either SSP or SSA or “SSP/SSA” to acknowledge that the two terms are interchangeable. The author is opposed to the term SSA, because the word “adenoma” has been traditionally understood by clinicians to be a dysplastic lesion (all conventional adenomas are dysplastic). However, more than 95% of all SSP/SSAs have no histologic dysplasia. Therefore, the term “SSP” engenders less confusion about the nature of these lesions. According to WHO, SSPs without dysplasia should be designated by pathologists as “SSP without cytological dysplasia.”

Less than 5% of SSPs have a region or portion that is histologically (and endoscopically) distinct from the SSP portion of the lesion in that it looks precisely like a conventional adenoma. In the past, such lesions were sometimes designated “mixed hyperplastic-adenomatous polyps.” The word “mixed” was a useful and accurate descriptor because these lesions are literally a mixture of SSP and conventional adenoma. According to WHO, these lesions should be designated as “SSP with cytological dysplasia,” and they are believed to represent a more advanced stage in the polyp-cancer sequence. About half of all serrated pathway cancers demonstrate microsatellite instability, generally attributable to epigenetic (hypermethylation driven) inactivation of the MLH1 gene.^3,4 The SSP with cytological dysplasia has a high prevalence of microsatellite instability, which microdissection studies show is frequently localized to the dysplastic portion of the lesion.6

The traditional serrated adenoma (TSA) is a rare lesion, located primarily in the left colon, and is the only consistently dysplastic member of the serrated class. The molecular profile of TSA is variable and TSA is relatively poorly understood compared to SSP and HP.7

Problems with Pathologic Interpretation of Serrated Class Lesions

The pathologic distinction between HP and SSP is subject to marked interobserver variation between pathologists.^8-10 The principal histologic distinction between HP and SSP is in crypt morphology, with crypts being straight and non-dilated in HP while SSP demonstrates dilation, distortion, and/or lateral crypt growth. The first problem in pathologic differentiation of HP from SSP arises because different expert bodies have different definitions (none of which have been validated) of the number of abnormal crypts or the percentage of abnormal crypts that must be present to identify SSP. The second problem is that when the number of affected crypts is small, there is marked interobserver variation between pathologists (even experts) in interpreting HP versus SSP.^8-10 A third problem is that some pathologists are either unaware of or refuse to acknowledge SSP. Thus in a multicenter trial from the U.S. and Germany involving > 7000 screening colonoscopies, some centers never reported SSP, though there were multiple HPs > 1 cm in size.¹¹ Within centers, the percentage of serrated class lesions called SSP has often increased steadily over the past decade, suggesting that awareness of SSP among pathologists is increasing.¹² These problems with differentiation of SSP from HP have created uncertainty among clinicians regarding the reliability of pathologic assessment of serrated class lesions, so that some clinicians treat HPs > 1 cm removed from the proximal colon as SSP and guidelines support this practice.²

The traditional serrated adenoma (TSA) represents another challenge for the clinical pathologist. As TSA is the only consistently dysplastic lesion in the serrated class and commonly has a villiform growth pattern, in clinical practice it is commonly misidentified as a tubulovillous conventional adenoma. Thus, many clinicians have never seen the term “traditional serrated adenoma” on a pathology report.

Endoscopic Detection of SSP

Colonoscopic detection of SSP is subject to even more marked variability between colonoscopists than detection of conventional adenomas.^12,13 SSPs are invariably sessile or flat, and many large SSPs are almost completely flat. SSPs are pale in color, and similar in colon to the surrounding mucosa, though the lesions typically obscure the colonic vascular pattern.^14,15 The surface texture of serrated class lesions is usually slightly rougher and more granular than the normal mucosa, which contributes to detection. A “cap” of adherent mucus is often an important clue to detection of serrated class lesions. HP and SSP share many endoscopic features, and are more easily distinguished from conventional adenomas than from each other. The Narrow band maging International Colorectal Endoscopic (NICE) classification for narrow-band imaging (NBI) optical diagnosis of colorectal polyps presents criteria for differentiation of conventional adenomas from serrated class lesions, but makes no attempt to differentiate HP from SSP.¹⁶ In NICE, serrated class lesions are distinguished by having no blood vessels on their surface, or only a few lacy blood vessels that course past multiple pits, uniform or relatively uniform sized pits, and pale color (Figure 1). The NICE classification has been utilized in multiple studies to accurately distinguish serrated class lesions from conventional adenomas.^17-19 Recently, the Workgroup serrAted polypS and Polyposis (WASP) classification has been developed to distinguish SSP from HP. Features that distinguish SSP, particularly when all are present, include large open pits, an irregular surface, indiscrete edges, and “cloud-like features” (Figure 2).²⁰ Endoscopically, the sessile serrated polyp with cytological dysplasia presents as regions that are partly NICE Type I and partly NICE Type 2 (Figure 3). Accurate detection of serrated class lesions depends on excellent bowel preparation, a colonoscopist with a complete understanding of the spectrum of endoscopic appearances of SSP, and a high definition colonoscope. Meticulous technique in looking behind folds, achieving adequate distention, and cleaning up pools of residual liquid and fecal debris are essential.²¹ When the first examination of the right colon reveals lesions, a second repeat examination in either the forward or retroflexed view should be considered.^22,23

Optimal Techniques for Resection for SSP

The CARE study evaluated predictors of incomplete colorectal polyp resection for lesions 5 to 20 mm in size.²⁴ Predictors of incomplete resection included larger polyp size, the endoscopist, and serrated histology. The overall risk of incomplete resection of serrated class lesions was 31%, compared to 7% for conventional adenomas, and half of serrated class lesions 10-20 mm in size were incompletely resected. The methods of endoscopic resection in the CARE study were not described.

The challenge in resecting serrated class lesions almost certainly arises because of their indistinct edges. With resection of large lesions, particularly in piecemeal fashion, the operator can lose track of the perimeter of the lesion and thereby fail to achieve complete resection.

In contrast to CARE, 2 recent studies have found that endoscopic mucosal resection (EMR) eradicates SSP as effectively as it treats conventional adenomas.^25,26 One included lesions only ≥ 20 mm in size,²⁵ and one included predominantly 10-20 mm lesions.²⁶ The keys to effective resection appear to be submucosal injection with a contrast agent (indigo carmine or methylene blue) and use of a high definition scope. These tools allow the endoscopist to effectively demarcate the lesion perimeter and keep track of residual abnormal crypts as the resection proceeds (Figure 4). These studies indicate that colonoscopists should have a low threshold (10 mm) for performing EMR for serrated class lesions.

Follow-up of Serrated Lesions Table 5.

There are very few observational studies describing the World Health Organization Criteria risk of cancer or advanced neoplasms after resection for Serrated Polyposis of serrated class lesions. Early recommendations will certainly be adjusted as new data become available. The U.S. Multi Society Task Force recommendations (Table 3) rely heavily on the pathologist’s report of HP versus SSP, though they endorse the practice of treating HPs ≥ 10 mm from the proximal colon as SSP.² This is particularly appropriate when clinicians rarely see SSP reported by their pathologists.

The National Institutes of Health expert consensus panel recommendations suggest that clinicians consider the size, histology, number, and location of serrated class lesions to choose a surveillance interval (Table 4).³ Proximal location, increasing number of lesions, increasing lesion size, pathologist interpretation of SSP over HP, and SSP with cytological dysplasia are all considered to have predictive value. Either set of recommendations represent a reasonable framework for choosing post polypectomy surveillance intervals after resection of serrated class lesions.

Choosing appropriate surveillance intervals is no substitute for adequate detection during baseline examinations. Overall, detection of serrated class lesions is reasonably correlated with detection of conventional adenomas,²⁷ and the primary measure of mucosal inspection quality should be the adenoma detection rate (ADR).²⁸ Currently, although detection of serrated lesions is considered very important, the use of a specific target for detection of serrated lesions is not feasible because it would need to be confined to the proximal colon (and therefore subject to endoscopist inaccuracy in assessing location) and the marked pathologist interobserver variation in differentiating SSP from HP.

Serrated Polyposis

Serrated polyposis (formerly hyperplastic polyposis syndrome) is by far the most common polyp syndrome in clinical practice.^29,30 The WHO presents 3 criteria for the diagnosis of serrated polyposis (Table 5).5 The diagnosis is frequently missed in clinical practice, and high sensitivity requires counting the number and size of lesions by location, and comparing to the WHO criteria.

The risk of cancer in serrated polyposis is most related to the number of large proximal colon SSPs and the presence of SSPs with dysplasia.29,30 Patients with serrated polyposis have a significant risk of colorectal cancer that can be managed by effective colonoscopic surveillance, usually performed at 1-2 year intervals.29,30 First-degree relatives of patients with serrated polyposis should undergo an initial screening colonoscopy at age 40, and then every 5 years if the baseline examination is negative.

Summary and Conclusions

The serrated or hypermethylated pathway to colorectal cancer proceeds through a distinct class of precursor lesions with unique molecular, histologic and endoscopic appearances. A full understanding of the spectrum of endoscopic appearances, as well as methods of effective resection, are essential to modern colonoscopic management of serrated lesions and to effective colonoscopy in general. EMR using a contrast agent and a high definition colonoscope effectively eradicates serrated class lesions. Endoscopists should have a high level of suspicion for serrated polyposis in patients with multiple serrated lesions, and compare polyp counts to WHO criteria for diagnosis of this syndrome.

Unusual Causes Of Abdominal Pain, #10

Unusual Causes of Abdominal Pain

April 2016 • Volume XL, Issue 4

Malorie Simons,

Sean Fine

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Malorie Simons, MD, Department of Medicine, Sean Fine, MD, Division of Gastroenterology, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI

CASE

An 89 year-old woman with a past medical history significant for a recent unprovoked deep vein thrombosis (DVT) started on Xarelto (Rivaroxaban), presented with worsening abdominal discomfort and generalized weakness. Physical exam was notable for conjunctival pallor, severe dyspnea on exertion and right lower extremity swelling without pain or erythema. Her abdomen was tender to palpation in the right upper quadrant. Laboratory data revealed anemia with a hemoglobin of 8.4 g/dl(normal 11-15/ dl), platelets 268 k/cmm (150-400k/cmm), transferrin saturation 6% (normal 15-50%), iron level 22ug/ dl (normal 37-170) ug/dl, ferritin 13 ng/dl (normal 10-120 ng/dl). Fecal occult blood test was positive. Endoscopy was unremarkable for any source of anemia. Colonoscopy uncovered multiple areas of prominent intramural mucosal hematomas along the transverse and ascending colon (Figure A, B, C).

No interventions were performed on the colonic hematomas. The patient’s remote history of a DVT prompted concern for a possible hyper or hypocoagulable state, but further workup which included a CT scan of the abdomen and pelvis did not demonstrate any malignancy or possible alternative explanation for the colonoscopy findings. Xarelto was stopped and the patient was bridged to warfarin to continue treatment for her recent DVT. One month after discharge, she was seen in the outpatient gastroenterology clinic. She was asymptomatic and her hemoglobin normalized.

ANSWER AND DISCUSSION

Colonic intramural hematomas are a rare complication of anticoagulation therapy. Most intramural hematomas associated with anticoagulation therapy occur in the small intestine causing pain, bleeding, anemia and at times, bowel obstruction. The literature associating Novel Oral Anticoagulants (NOACs) with colonic intramural hematomas is scarce. Kwon et al. (2014) reviewed 32 case reports of colonic hematomas, 8 of which were anticoagulant induced, with warfarin being the most common culprit.¹

NOACs are gaining more popularity due to ease of use and fewer monitoring requirements. Most studies thus far have compared NOACs to warfarin, but not to each other. The ROCKET AF trial investigated the use of Rivaroxaban in stroke prevention in patients with atrial fibrillation. One noted side effect was a higher incidence of major gastrointestinal bleeding when compared to patients in the warfarin cohort.² In the ARISTOTLE trial, Apixaban was shown to not only be more effective than warfarin at preventing stroke, but also safer in terms of major gastrointestinal bleeding.³ From these studies, it appears that Apixaban may provide an optimistic alternative for anticoagulation with the most favorable GI side effect profile; however, further studies comparing NOACs to one another will need to be performed.

For our patient, we suspect that Rivaroxaban led to the colonic hematomas that were ultimately responsible for the GI blood loss and abdominal discomfort. Although most anticoagulant associated intramural hematomas of the GI tract are linked to warfarin, and most often occur in the small intestine, this case reminds us that intramural colonic hematomas are a real entity in the setting of NOACs as well.

A Case Report

Eosinophilic Gastroenteritis Presenting as Gastric Pneumatosis

August 2016 • Volume XL, Issue 8

Drew Triplett,Nyla Hazratjee,Sangeeta Agrawal

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Drew Triplett, DO, Nyla Hazratjee, MD Sangeeta Agrawal, MD, FACG, FASGE, AGAF Dayton, VA Medical Center, Wright State University, Department of Internal Medicine, Division of Gastroenterology

INTRODUCTION

Eosinophilic inflammation of the gastrointestinal tract is a rare disease with an incidence of 22 to 28 per 100,000 persons. More unusual still is its presentation with gastrointestinal pneumatosis. Eosinophilic gastroenteritis (EG) can present with varying symptoms, compounding the difficulty of diagnosis. Generally, patients present with years of gastrointestinal symptoms including growth retardation, failure to thrive, delayed puberty or amenorrhea in children and abdominal pain, diarrhea or dysphagia in adults.1 Here we describe a case of a male patient, initially diagnosed with mesenteric ischemia, who was later found to meet criteria for eosinophilic gastroenteritis presenting as gastric pneumatosis and colonic pneumatosis, both of which have not previously been described in human adults. He achieved resolution of gastrointestinal symptoms with treatment with prednisone.

Case Presentation

A 76-year-old Caucasian male presented to our hospital with acute abdominal pain, nausea and vomiting of three to five days duration. He carried a recent history of right hemicolectomy for intestinal pneumatosis thought to be related to ischemic colitis four months prior to admission. His physical exam was normal except for diffuse abdominal tenderness on palpation. On initial laboratory evaluation, his white blood cell count was 8,500 and hemoglobin 10.5g/dL. The patient had a non- contrast computed tomography (CT) of the abdomen and pelvis which demonstrated gastric pneumatosis, portal venous gas in the right and left hepatic lobes, and mesenteric gas in the right upper quadrant that was not seen on a CT scan nine days earlier.

Non-surgical management was pursued, though the patient continued to have symptoms. Due to the lack of clinical improvement, esophagogastroduodenoscopy (EGD) was performed three days later with findings suggestive of ischemic gastritis involving the gastric fundus and body, and biopsies were obtained from the stomach and duodenum. It was initially thought that chronic mesenteric ischemia was the likely cause of these findings and the patient was treated conservatively. However, pathology showed increased eosinophils in the lamina propria suggestive of eosinophilic gastritis, while staining for Helicobacter pylori was negative. Stool studies for ova and parasites returned negative. With these findings, a thorough chart review discovered that the recent hemicolectomy pathology report also revealed increased eosinophils within the submucosa, muscularis propria and serosa consistent with eosinophilic colitis. The patient also had a peripheral eosinophilia at 6.5%. He was treated with intravenous methylprednisolone that was later transitioned to oral prednisone once he was able to tolerate a regular diet. He continued to improve clinically and discharged 12 days after initiation of steroids to an extended care geriatrics facility.

Discussion

Eosinophilic gastroenteritis is an eosinophilic inflammation of the gastrointestinal tract and can have a varied presentation depending on the location and depth of the eosinophilic infiltration. The diagnosis of EG can be difficult and delayed due to the uncommon nature and its varying presentation as well as difficulty in obtaining pathological diagnosis. Most patients with eosinophilic gastroenteritis present with a combination of abdominal pain, vomiting or diarrhea which are not specific to this disease process. The diagnosis of EG is based on four criteria including: presence of gastrointestinal symptoms, eosinophilic infiltration of gastrointestinal tract, exclusion of parasitic disease and absence of other systemic involvement.¹ Gastrointestinal symptoms may be severe in some cases and can differ depending on the site and layer of involvement.² For example, ascites has been reported as the presenting symptom but more common presenting symptoms include diarrhea, weight loss and abdominal pain.³ Eosinophilic gastroenteritis presenting with colonic pneumatosis is previously described in one child with eosinophilic colitis.⁴ Gastric pneumatosis related to eosinophilia is reported in four black and white lemurs in association with eosinophilic gastroenteritis.⁵

Once an index of suspicion has been established, histological evidence of eosinophilic infiltration is necessary to confirm the diagnosis.² Parasitic infection such as Anisakis simplex have been reported as a cause of eosinophilic gastroenteritis⁶ supporting the necessity to rule out parasitic infections prior to establishing a diagnosis. Eosinophilic gastroenteritis should be considered in patients with unexplained gastrointestinal symptoms and peripheral eosinophilia,² however peripheral eosinophilia is not always found in eosinophilic gastroenteritis.⁷ Furthermore, its presence as a diagnostic criterion is uncertain.² Treatment for both adults and children consists of corticosteroids, with improvement in symptoms usually seen within two weeks.² Other treatments that have been reported include montelukast, keitofen, sodium cromoglycate and humanized IL-5.^8-11

The finding of gastric pneumatosis can be seen in a wide range of conditions with some of the most common causes being infection, trauma and medications.¹² As noted above, it has been rarely associated with eosinophilic gastroenteritis.

CONCULSION

This case highlights a rare presentation of eosinophilic gastroenteritis complicated by intestinal wall pneumatosis and later gastric pneumatosis. It is thought that underlying eosinophilic gastroenteritis propagated the majority of this patient’s clinical course. Perhaps earlier recognition of eosinophilic gastroenteritis could have reduced morbidity and hospitalization stays. Clinicians should consider eosinophilic gastroenteritis in patients presenting with gastric pneumatosis.

Colorectal Cancer: Real Progress In Diagnosis And Treatment, Series #6

Endoscopic Management of Colorectal Cancer

August 2016 • Volume XL, Issue 8

Wei-Chung Chen,

Michael B. Wallace

With the advancement of new endoscopic techniques including endoscopic mucosal resection and endoscopic submucosal dissection, early colorectal cancer that presents with favorable features can be initially removed endoscopically without surgery. In this review we will discuss the expanding role of endoscopic resection in the treatment of colon cancer.

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers in the United States. Until recently, colon cancer found on endoscopic examination has been treated entirely with surgical resection. With the advancement of new endoscopic techniques including endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD), early CRC that presents with favorable features can be initially removed endoscopically without surgery. In this review we will discuss the expanding role of endoscopic resection in the treatment of colon cancer.

Wei-Chung Chen, MD, MPH, Michael B. Wallace, MD, MPH Department of Gastroenterology, Mayo Clinic, Jacksonville, FL

INTRODUCTION

Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer with an estimated incidence of 132,700 cases in the United States in 2015.¹ Most malignant neoplasms of the colon and rectum arise from non-invasive adenomatous polyps. Malignant colorectal polyps are defined according to the Vienna classification by the presence of cancer cells invading through the lamina propria into the underlying mucosa or submucosa (pT1).² With recent development and refinement of endoscopic techniques, endoscopic resection has played an increased role in the resection of early colon cancer. In particular, T1 colorectal cancer with favorable features can be removed by endoscopic techniques.

In this review, we will address various topics including initial endoscopic assessment of the colon lesion, histology of invasion of depth, risk factors associated with invasive colorectal cancer, endoscopic techniques to remove early colon cancer, and surgical treatment of early colon cancer.

Endoscopic Assessment

Given the potential for curative endoscopic resection, it is increasingly important to identify which lesions are non-invasive, superficially invasive, and deeply invasive. The depth of invasion guides management as non-invasive lesions can be treated by simple endoscopic mucosal resection, the superficially invasive lesions require en bloc endoscopic resection, and the deeply invasive lesions require surgery. Endoscopic inspection of the shape and surface patterns has now been well validated means to make accurate classification of invasion depth.

Colonic adenomas are classified as either polypoid or nonpolypoid type. Based on the Paris classification, polypoid lesions include pedunculated (0-Ip) and sessile-shaped (0-Is) lesions. Nonpolypoid lesions may be subdivided into superficially elevated (0-IIa), flat (0-IIb), depressed (0-IIc), and excavated or ulcerated lesions (0-III). Flat and particularly depressed polyps are more likely to harbor high grade dysplasia and invasive cancer.3 Using the Paris classification, 0-Ip and 0-Is can be removed by snare polypectomy. Nonpolypoid lesion such as 0-IIa and 0-IIb can be removed EMR en bloc or piecemeal. Depressed lesions categorized as 0-IIc, often signifying early cancer, can also be removed with ESD or en bloc EMR. Lastly, ulcerated lesions represent deep carcinoma and require surgical resection.

Superficial elevated lesions 20 mm or larger are termed lateral spreading tumors (LSTs). LSTs can be divided into granular LSTs, nongranular LSTs, or mixed- type based on surface appearance. Understanding the morphology allows the endoscopist to select the proper technique in removing the colon polyp. Nongranular LSTs are at highest risk for harboring invasive cancer.

Changes in pit patterns seen on the colon surface can aid the endoscopist in determining the degree of neoplasia and depth of invasion. Pit pattern are classically seen with the use of dye spray and are classified by the Kudo system. Type IIIs (small tubular or round pit pattern that is smaller than normal pit) and Type IIIL (tubular or round pit that is larger than the normal pit) are usually associated with tubular adenoma. Type IV (dendritic or gyrus-like pit) is associated with tubulovillous histology. Type V₁ (irregular arrangement) or Type V_N (loss or decrease of pits) is associated with intramucosal or invasive malignancy.⁴

Surface pit patterns have been incorporated into Narrow Band Imaging International Classification for Endoscopy (NICE) classification systems to aid in management of colonic neoplasia.⁵ There are three subtypes of the NICE classification, and it is organized based on color, vessel, and surface pattern. Type 1 2, and 3a can be treated endoscopically. However, Type 3b indicates likely deep submucosal invasive cancer and needs surgical operation for removal.⁶

Histologic Invasion Depth

Invasion depth of colorectal carcinoma predicts lymph node metastasis, and pedunculated lesions (Paris 0-Ip) having a lower risk for lymphatic spread than sessile or flat lesions (Paris 0-Is and 0-II). Two models were devised to classify colorectal cancer invasion depth: Haggitt classification for pedunculated lesions and Kikutchi classification for sessile or flat lesions.

Haggitt and colleagues stratified the invasion depth into levels 0-4, with carcinoma confined to mucosa (0), polyp head (1), neck (2), stalk (3), and invasion into submucosa of the underlying colonic wall (4).^7,8 For invasion depth levels 1, 2, and 3, there is absent lymph node metastases and local cancer recurrence. For patients with Haggitt level 4 invasion, 27% of cases harbored lymph node metastasis.^9,10

The other model devised by Kikutchi and colleagues assess the depth of submucosal cancer invasion by dividing the submucosa into thirds (SM1, SM2 and SM3). Colon cancer confine to upper third or SM1 has no risk of lymph node metastasis, but deeper invasion into the submucosa can increase to the risk of lymph node metastasis to up to 25%. Currently, colon cancer confined to the upper third of submucosa layer (SM1) is amendable to endoscopic resection, but deeper invasion into submucosa requires surgical resection.

Risk Factors of Invasive Colorectal Cancer

Different risk factors for invasive colorectal cancer and lymph node metastasis were introduced by different studies. Invasion into the deepest third of the submucosa (SM3) which likely correlates with a submucosal invasion ≥1mm, presence of lymphovascular invasion, location in the lower third of the rectum, poor differentiation, tumor budding, and incomplete polypectomy are independently associated with increased risk of lymph node metastasis and residual cancer and warrant a radical resection.^11-15

Endoscopic Mucosal Resection and Endoscopic Submucosal Dissection

EMR and ESD are current mainstay treatments for resection of neoplasia. Low-risk colorectal cancers harbor the following features: well to moderate differentiated, ≥2mm cancer-free margin and Haggitt invasion level 1-3. These are unlikely to develop recurrence or metastatic disease when amendable for en- bloc EMR with a disease-free and overall survival of 90- 96% and 89-96%, respectively.^16-20 On the other hand, Kikuchi SM3 and Haggitt 4 invasion level, submucosal invasion ≥1000µm, positive excision margin, lymphatic or venous invasion, and poor differentiation predict residual tumor and lymph node metastasis, warranting radical resection.^20-23

ESD is a well-established technique that is mostly performed in Asia although increasingly accepted in the West. In direct comparison with EMR, ESD has a lower neoplasia recurrence rate (14.5% vs. 2.1%).²⁴ and higher en-bloc resection rate. However, this comes at the costs of a higher perforation (0.8% vs. 1.6-4.9%) and bleeding rate (2% vs. 1.5-2.2%).25,26 Recent literature recommends colorectal ESD for neoplasia when en- bloc resection is difficult to achieve (mostly >20mm), for non-granular LST, Kudo V pit pattern, non-lifting neoplasia and invasive submucosal cancer ≥1000µm infiltration.²⁴

Endoscopic Mucosal Resection

Initially described in 1973, EMR is a technique used for resection of lesions confined to the mucosa or submucosa of the colon. Lesions limited to the mucosa and superficial layers of submucosa are more suitable for EMR.²⁷ Adenoma of the colon represents one of the most important premalignant lesions of the gastrointestinal tract. Compared to regular snare polypectomy, EMR has a higher successful complete resection rate for large colon polyps (> 2cm).²⁸ On the other hand, lesions that are greater than 2 cm may require piecemeal mucosal resection.

One of the important features of EMR involves submucosal fluid injection. Typically, a sclerotherapy needle is used to inject the fluid into the submucosa. This provides a cushion to protect the deeper layers of the colonic wall to prevent perforation and bleeding. Common agents used for lifting the base of the lesion include normal saline, hydroxypropyl methylcellulose, glycerol, 50% dextrose, hyaluronic acid, and hypertonic saline. Compared to normal saline, hypertonic solution seems to provide better and longer-lasting elevation. Methylene blue and indigo carmine are used to confirm if the resection is in the correct plane. Approximately, 3 mL to 10 mL of solution is needed to achieve adequate separation from the submucosa, and this reduces the risk of thermal and mechanical injury of the deeper layers. After submucosal injection, a snare is placed on top of the protruding lesion, and the lesion is resected using electrocautery with high-frequency current.

Approximately 5% of cases of large colorectal polyps after EMR can result in intraoperative/immediate bleeding or delayed bleeding (hours to weeks after the procedure).^29-31 Most delayed bleeding occurs within two weeks after EMR. Predictors associated with risk for post-polypectomy bleeding including polyp size greater than 1 cm to 2 cm, flat or laterally spreading lesions, pedunculated polyp with thick stalk, proximal colon lesions, resection technique, and coagulation status.³² Immediate bleeding can be controlled by several methods including dilute epinephrine, endoscopic clipping, and bipolar coagulation probe.

In the setting of delayed bleeding, patients can be managed conservatively if hematochizia ceases at the time of admission because rebleeding from the EMR site is uncommon. If there is no sign of active bleeding or gross blood noted during bowel preparation, colonoscopy can be deferred unless patient requires re-initiation of anticoagulation agent. Otherwise, for patients with ongoing hematochezia or other signs of GI bleeding, urgent colonoscopy should be performed.

A recent systemic review and meta-analysis indicates that the general recurrence rate of colorectal lesions is around 13.1% after EMR.³³ Piecemeal resection was associated with higher recurrence rate compared to en-bloc technique, with odds ratio of 4.4. Although some studies suggest that the application of prophylactic APC at the resection edge results in lower risk of recurrence of colonic lesions, more data is needed to confirm the optimal methods.³⁴ Fortunately, most recurrences after EMR or ESD can be treated with further resection, resulting in long term cure.²⁵

Endoscopic Submucosal Dissection

ESD is primarily used for lesions confined to the mucosa or superficial submucosa measuring greater than 20 mm in diameter. ESD has the advantage of achieving en-bloc resection regardless of lesion size, which results in lower recurrence.36 It is performed when the lesion needs to be resected en bloc to evaluate the histological features. Granular LST, nodular type measuring ≥30 mm or nongranular LST measuring ≥20 mm are also lesions to be considered for ESD.³⁷ ESD is also indicated for lesions that are difficult to resect with conventional EMR, including lesions that show non-lifting signs after submucosal injection and recurrent lesions at the same location.³⁶ The technique is not suited for lesions with deep submucosal invasion. It should be noted, that there is no randomized controlled trial of EMR versus ESD for colorectal neoplasia. Until such data is available, the optimal method of resecting such lesions remains unknown.

At the start of the procedure, the lesion is marked circumferentially by applying soft coagulation current. Submucosal injection is performed initially to provide a fluid cushion. The main solutions used for ESD are normal saline, glycerol, and hyaluronic acid. Normal saline is usually adequate for gastric ESD as the gastric wall is thicker. However, for colon and esophagus, longer lasting solution is needed to lift the mucosal wall.38 After the injection, a mucosal incision is made with short needle knife, and afterward, the lesion is further dissected from the other layers of the bowel wall by using electrocautery knives. There are two types of ESD knives used during procedure including needle knives and insulated tip knives.³⁸ It is essential to continue the dissection through the submucosal layer and avoid injury to the muscularis propria. Carbon dioxide insufflation is recommended because this is rapidly reabsorbed in the event of perforation. In a case- control series, the use of carbon dioxide for insufflation was associated with shorter operating times, lower use of sedation medication, and reduced procedural and post-procedural pain.^39,40

There are many risk factors that strongly correlate with increased difficulty in performing this procedure. One prospective study with 247 lesions demonstrates that location of the lesion particularly at the hepatic and splenic flexure, locally recurrent lesion, tumor size = 50 mm, and tumor spreading across ≥ 2 folds were strong independent risk factors for longer procedure duration or perforation.⁴¹

Recent studies have focused on the efficacy and safety of colorectal ESD. A recent meta-analysis and systemic review of 22 studies provided data on 2841 ESD lesions. Analysis from the study shows that ESD is extremely effective in achieving complete en-bloc resection in 88% of lesions that are ≥ 20mm.⁴²

Endoscopic Versus Surgical Treatment for Colorectal Cancer

No randomized controlled trials have compared endoscopic resection vs. transanal full thickness resection vs. radical resection. EMR of high-risk T1 colorectal cancer had a reported recurrence rate of 20.1% compared with 3.7% following radical resection.⁴³ Based on recent study, endoscopic resection is only acceptable for low-risk T1 colorectal cancer.^20,43

CONCLUSION

For early T1 colorectal cancer, EMR and ESD offer safe and effective alternatives to surgical resection. It is critical to select the appropriate patient to undergo endoscopic resection, and this can be accomplished through careful endoscopic and histologic assessment. Currently, colon cancer confined to SM1 is amendable to endoscopic resection, and deeper invasion into submucosa requires surgical resection. Additional studies looking at the complete resection rate, recurrence, and complications comparing EMR and ESD with surgical treatment for early colorectal cancer is warranted.

Gastrointestinal Motility And Functional Bowel Disorders, Series #18

Review of Esophageal Rings: Diagnosis and Treatments

August 2016 • Volume XL, Issue 8

Majd Michael,

Richard W. McCallum